Nicardipine possesses a coronary dilator activity and a cerebral vascular dilator activity, and is a medicament useful for curing cerebral vascular disease, hypertension, and angina pectoris. Since nicardipine or its salt has a good solubility in the first fluid of Japanese Pharmacopeia IX (a fluid of about pH 1.2 prepared by adding 24.0 ml of diluted hydrochloric acid and water to 2.0 g of sodium chloride to make 1,000 ml of the solution), it exhibits sufficiently the medical activity in usual preparations but since nicardipine is sparingly soluble in the second fluid of Japanese Pharmacopeia IX (a fluid of about pH 7.5 prepared by adding 6.0 ml of diluted hydrochloric acid and water to 35.8 g of disodium hydrogenphosphate to make 1,000 ml of the solution) and is practically insoluble in intestinal juice, it is difficult to prepare an effective, long acting preparation of nicardipine.
Since a long acting preparation has many therapeutic advantages such as the reduction in dosing frequency of the medicament, long acting effective concentration of medicament in blood, etc., various general long acting preparations have hitherto been developed. For example, there are preparations having compounded therewith a large amount of a material which does not disintegrate in the stomach or intestines, a preparation formed by coating pellets or tablets with a water repellent, and also a preparation formed by mixing a medicament with a sparingly soluble or hydrophilic high molecular compound or by adsorbing the high molecular compound onto a medicament, whereby the medicament is gradually released. However, in the case of a medicament having a low solubility in an intestinal juice such as nicardipine or a salt thereof, a long acting effect cannot be obtained by such conventional long acting preparations. That is, the application of the foregoing conventional long acting technique to such a medicament may cause only the reduction of bioavailability and hence, in the case of such a medicament, it is necessary to compound therewith an additive for improving the solubility thereof in an intestinal juice to improve the solubility of the medicament.
Therefore, various processes of producing long acting preparations of nicardipine have been proposed. For example, there is a process of producing a long acting preparation of nicardipine by dissolving nicardipine in water or organic solvent(s) together with (a) hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), etc., and further, it desired, (b) polyethylene glycol, a surface active agent, etc., removing water or the organic solvent to form solid material, pulverizing, if necessary, the solid material, and then adding thereto polyethylene oxide (PEO); or by adding PEO to nicardipine and the components (a) and (b), dissolving the mixture in water or organic solvents(s), removing the water or the organic solvent(s) to form a solid material, pulverizing, if necessary, the solid material, and then forming the preparation using the solid material or the pulverized solid material (Japanese Patent Application (OPI) No. 49,314/'81) and a process of producing a long acting preparation of nicardipine by, if necessary friction-pulverizing nicardipine crystals and adding a pH-dependent additive, diluents, etc., to the nicardipine crystals before or after pulverizing them (Japanese Patent Application (OPI) No. 133,217/'81). However, the preparations obtained by these processes are objectionable in that the concentration of the medicament does not reach an effective plasma level in a short period of time after the administration i.e., the clinically effective plasma level is not sufficiently maintained, the intersubject variation of plasma of concentration is large, etc.